In trauma and sepsis, in addition to the conspicuous injuries or signs of infection, there are also metabolic changes. These changes can be divided into an early so-called ebb phase followed later by a so-called flow phase. In the ebb phase (shock phase), which can last for 1-3 days after the incidence of the injury, there exists a reduced energy turnover, increased lipolysis, hyperglycemia, elevated catecholamine release and hormonal maladaptation, circulatory effects with decreasing blood pressure, reduced tissue perfusion and oxygen consumption, hypoxia, acidosis, increased body weight as a result of fluid and urine retention and a reduced body temperature. Protein synthesis is also reduced as well as blood albumin and amino acid concentrations.
After about 3 days, the flow phase appears which can last for 1-4 weeks. The flow phase is characterised by an increased energy turnover, increased release of substrates, negative nitrogen balance, rise in blood pressure, increased oxygen consumption and elevation of body temperature. Protein synthesis is reduced in mild trauma whilst both synthesis and breakdown increase in major trauma. Breakdown dominates resulting in a negative nitrogen balance which can reach 0.3-0.6 g nitrogen per kg body weight and day. This is equivalent to approximately 1.2-2.4 kg muscle wastage per day in a normal individual.
If the catabolic component of the flow phase continues for too long, a life threatening situation can develop with substantial losses of fat and muscle tissue as well as impaired wound healing and defence against infection (Ljusk S. Eriksson, Mossberg T., Wahren J.; pp 99-117, Klin Nutr Almq & Wiks 1987).
The concentration of glycogenic amino acids (such as alanine, glycine, serine and glutamic acid) drops in the plasma whilst a simultaneous increase in the plasma levels of branched chain amino acids (such as leucine, isoleucine and valine), aromatic amino acids (such as phenylalanine, tyrosine and tryptophan) as well as methionine, is observed. An approximately 50% reduction of the intracellular glutamine concentration is also typical. The above mentioned changes can partly be explained as disturbances in transport over the cell membrane. Alanine and glutamine are taken up and metabolised by the gut mucosa and the liver. In the liver they are utilised for, amongst other things, gluconeogenesis. In burn patients the splanchnic (liver and gut) uptake of amino acids is increased approximately 2-6-fold compared to a healthy control. The protein catabolism, which is evident mainly as increased urea production, not only affects striated muscles and visceral proteins but also smooth muscles such as those found in the gut wall and in the respiratory pathways. This situation can negatively affect vital bodily functions as well as secretory transport in the bronchii, with secretory stagnation and development of pneumonia, a common post-traumatic complication.
The gut mucosa is important not only for the selective and active absorption of different nutrients, but also as a barrier against foreign organisms and toxins. In recent years, it has been shown that the barrier function of the gut mucosa deteriorates in association with major trauma and sepsis. Furthermore, both cytotoxic chemotherapy and radiation therapy have a deleterious effect on gut mucosal function. Intravenous nutritional therapy, which is applied when the patient has difficulties to eat or assimilate orally administered food, has been shown to contribute to atrophy of the gut mucosa. Gut atrophy appears in laboratory animals and in man after intravenous feeding. This can increase the risk for translocation of bacteria over the gut mucosa with consequent risk for sepsis and increased mortality.
Atrophy of the gut combined with simultaneous translocation of bacteria over the gut mucosa is most likely in patients who have suffered major trauma and extensive clinical intervention, in sepsis, in major burn injuries and even after radiation therapy and/or cytotoxic chemotherapy in patients with abdominal or urogenital tumours. Patients with inflammatory diseases of the gut such as ulcerative colitis and morbus Chron also run the risk of being stricken by life threatening infections caused by atrophy of the villi and consequent development of ileus with toxic dilatation and release of bacteria into the peritoneum.
The observation of a marked decline in the intracellular concentration of glutamine in muscle following trauma and sepsis initiated interest in glutamine metabolism and its significance. It has been shown that glutamine is an important energy substrate in intestinal tissue and that glutamine utilization increases in the catabolic state. In studies on experimental animals it has been demonstrated that glutamine administration can prevent a fall in plasma and muscle glutamine concentrations following trauma. Further, an accelerated mucosa recovery after injury induced by 5-fluorouracil was observed in rats when glutamine was added to the intravenous nutrition solutions ('Dwyer ST et al, Clin Res 367a, 1987).
During an international symposium "Glutamine metabolism in health and disease", Jan. 26-27, 1990, in San Antonio, Tex., U.S.A., it was reported that in human subjects, post-operative glutamine supplementation of a total parentoral nutritional regimen improved nitrogen balance and counteracted the decline in protein synthesis usually seen post-operatively. Further it was reported that a number of positive effects had been observed in patients undergoing bone marrow transplantation who were given considerable amounts of glutamine.
In a patent for the treatment of catabolic dysfunction in an animal, a composition including 5-30 g of L-glutamine and/or 5-25 g of alpha-keto glutaric acid is claimed (WO 87/01589). Another patent comprises aqueous solutions for parenteral nutrition which preferentially contain glutamine together with other organic nitrogen-containing compounds (WO 87/03806). Furthermore, the presentation of glutamine in the form of dipeptides has been patented (see EP 87750 and DE 3108079).
The gut has an active endogenous microflora of which the majority of the organisms are facultative or obligatory anaerobes. This means that the major products of fermentation are the short-chain fatty acids (SCFA), mainly acetic acid, propionic acid and butyric acid. The substrates for this fermentation are the carbohydrates that reach the large intestine.
In so-called germ-free rats there is an atrophy of the gut mucosa. These rats also have a low endogenous production of SCFA which represents only about 1% of the production seen in normal rats (Hoverstedt and Midtvendt, J. Nutr. 116, 1772-76, 1986).
A fiber-free diet (one week) or total parenteral nutrition (two weeks) reduces the fecal loss of SCFA in man by 50% and 80%, respectively (Hoverstedt, Symposium, held at The Wennergren-Gren Center, Stockholm, Sweden, Jun. 1th-4th,1988).
Some experiments with SCFA-enriched nutritional solutions have been described in the literature. In all cases but one the experiments were carried out in animals that had been subjected to small bowel resection and given intracolonal or intracaecal infusions.
In a study of Koruda et al. (Am. J. Clin. Nutr. 51,685-9, 1990) SCFA-enriched total parenteral nutrition was employed, but since was no fat in the regimen, the diet was not balanced (lacking essential fatty acids). Furthermore, a mixture of SCFA (acetate, propionate and butyrate) was used in which acetate and propionate were in higher concentration than butyrate. These shorter acids have been shown to be more toxic than butyrate.
It has been suggested (WO 87/04074) that protein accretion or nitrogen retention can be promoted in the case of a hypocaloric diet by the administration of growth hormone.
In a study with intravenously fed rats, an increase in mucosa protein was observed in the small bowel and in the colon following the simultaneous administration of L-glutamine and epidermal growth factor (Jacobs D. O. et al. Surgery 104 (2), 358-364 (1988)). IGF-1 has been shown by O'Sullivan et al. (Endocrinology 125: 2793-95 81989) to prevent weight loss in starved mice, whereas GH (bovine) was ineffective in this situation. A relative increase in kidney and spleen weights has been reported for GH and IGF-1 treated rats (Skonner A. et al. Endocrinology 124, 2519 (1989).
It is quite clear, however, that several of the problems mentioned above have until now not been solved with existing nutritional therapy.
At present there is no clinical application of a growth factor alone or together with glutamine and/or a short- or medium-chain fatty acid for the improvement of gut function or for the combination having anabolic effects.